Benzene sulphonamidyl compounds of sulphanilamide, salts and derivatives thereof, and methods of production



Patented Apr. 28, 1942 UNITED STATES PATENT OFFICE BEN ZEN E SULPHONAMIDYL COMPOUNDS OF SULPHANILAMIDE, SALTS AND DERIV- ATIVES THEREOE'ANDMETHODS OF PRO- DUCTION Sanford M. Rosenthal and Hugo Bauer, Washington, D. 0., assignors to Government or the United States of America, represented'by the Secretary of the Treasury No Drawing. Application June25, 1937,

Serial No. 150,424

12 Claims.

(Granted under the act of March 3, 1883, as amended April 30, 1928; 370 O. G. 757) in which X is a whole number greater than one, R is either hydrogen or a non-acetyl organic radical, and R is an organic radical; as well as salts of such compounds and the method of preparation of the same.

The present invention includes a new therapeutically active compound para-aminobenzene sulphonyl sulphanilainide which may be termed the N [sulphanilyl]-sulphanilamide, and which I we have called di-sulphanilamide herein and therapeutically active salts and derivatives of this compound which are superior in certain respects to sulphanilamide (para-aminobenzene sulphonamide further known under the trade names Prontylin, Sulphamidyl and Sulphonamide-P), and which may serve to replace sulphanilamide or its known derivatives in pharmaceutical preparations and in medical applications. Di-sulphanilamide and some of the related compounds show a higher degree of therapeutic action in the treatment of certain bacterial infections, and possess the advantage of a greater margin of safety than sulphanilamide. The products of the invention are intended to be administered by mouth or by injection. Disulphanilamide is amphoteric in character so that it can form compounds with either acidic or basic substances. While the term Di-sulphanilamide is used herein as representative for purposes of definition, it is intended to be interpreted as including compounds such as the derivatives of this substance with organic or inorganic acids or bases.

The substance 4-sulphonamide benzol-azo-2- 4diaminobenzo1 (also known by the trade name Prontosil) was shown by Domagk in 1935 to possess curative action in stretptococcal infections (Angewandte Chemie 1935, vol. 48, p. 657).

Trefouel, Nitti and Bovet showed that the azo linkage in this substance was not necessary for chemotherapeutic action, and that p-aminobenzene sulphonamide (or sulphanilamide) possessed similar curative action in streptococcal infections (see Compt. Rend. Soc. de Biol., 1935, vol.

120, p. 756. thatsulphanilamide is more active than Prontosil, and that a new compound para-aminobenzene sulphonyl para-aminobenzene sulphonqamide which we have prepared for the first time,

and which We have called Di-sulphanilamide, is more effective in streptococcal and meningococcal infections when injected subcutaneously than is sulphanilamide while at the same time it is less than one-fifth as toxic. (See Rosenthal, S. M., Bauer, Hugo, and Branham, S. E. U. S. Pub. Health Reps, 1937, vol. 52, pp. 6626'71.)

The general method of preparing these compounds is as follows:

Acetanilide para-sulphochloride is condensed with sulphanilamide or its derivatives, of the general formula HzNCsHiSOeNHR (R is hydrogen or an organic radical). The condensation products of the general formula are deacetylated in the usual way heating with mineral acids, such as hydrochloric acid. The compounds obtained by this procedure may be the final products or they may be'further substituted in the free amino group with organic radicals, employing well known methods for such substitution.

The invention includes (1) p-Aminobenzene sulphonyl-sulphanilamide (di sulphanilamide) and its alkali salts.

(2) Derivatives of the Di-sulphanila-mide, in which the sulphonamide group is substituted by radicals, e. g. (a) ethanolamide-derivative (b) glycine-derivative.

(3) Derivatives of the di-sulphanilamide, in which the amino group is substituted by radicals, e. g., formaldehyde sulphoxyl, benzyl, car boxybenzyl and para-aminobenze'ne sulphonyl (tri-sulphanilamide) derivatives.

(1a) The di-sulphanilamide itself is attained as follows:

Seventeen grams of the well-known sulphanilamide (see P. Gelmo, J our. fur praktische Chemie, vol. 77, p. 369, 1908) and 25 grams of acetanilide para-sulphochloride (see J. Stewart, Jour. Chemical Society, London. vol. 121, p. 2558, 1922) are dissolved in a mixture of 150 ccm. acetone and 150 ccm. water. 'Then 1.0 grams of a weak base, such as sodium bicarbonate, are added. The reaction takes place under development of carbon dioxide. The mixture is vigorously stirred until the sodium bicarbonate has disappeared and the crystallization of the new condensation product takes place. By adding of water the precipi- We have shown experimentally tation of the acetyl di-sulphanilamide is completed. This acetylated compound however, has so little curvative effect that it can not be considered a therapeutically active derivative within the scope of this invention. Hence after suction and washing with water, the acetyl derivative is suitably deacetylated. This may be advantageously effected by boiling with 100 com. of hydrochloric acid (sp. gr. 1.08) until dissolved, which will take about half an hour, resulting, after cooling, in the separation of the hydrochloride of the di-sulphanilamide in long'needles.

To get the free di-sulphanilamide, the hydrochloride is dissolved in water, preferably by suspending it in a limited quantity of water and effecting solution by carefully adding sodium carbonate solution, and the di-sulphanilamide is precipitated preferably with a weak acid such as acetic acid. The yield is about grams.

Di-sulphanilamide is very sparingly soluble in cold water, Well soluble in hot water and may be recrystallized out of hot water. The melting point is 130 C. It has the formula C12H1304N3S2 and is constituted as follows:

(lb) The sodium salt of the di-sulphanilamide can be obtained by dissolving di-sulphanilamide in the calculated amount of sodium hydroxide and precipitating with alcohol and ether. The sodium salt is a white powder which is readily soluble in water with alkaline reaction. Here the sodium should be regarded as linked to a nitrogen of the compound, as the nitrogens are the elements of the compound to be expected to assume acid functions in the formation of substituents. Similar procedure may be used to obtain other alkali salts.

(2a) The di-sulphanil ethanolamide is prepared by the action of acetanilide-p-sulphochloride on the ethanolamide derivative of the sulphanilamide. The latter is attained as follows:

To 40 grams of ethanolamine, diluted with 160 com. of water, '70 grams of acetanilide-p-sulphochloride is added. The reaction takes place under development of heat. After cooling, the mixture solidifies by crystallization of the condensation product. It may be recrystallized out of water, acetone, acetic ether. It melts at 120 C.

The deacetylation is made by heating with the calculated amount of hydrochloric acid (sp. gr. 1.08) for half an hour. By neutralizing with sodium bicarbonate the sulphanilethanolamide is attained as a crystallized white powder. The formula is CeH1203N2S, the constitution is as follows:

NHz-OSOzNllCzHsOH This compound may also be termed the sulphanilyl ethanolamide, or the N -[hydroxyethyl]- sulphanilamide. It may be purified by crystallizing out of acetic ether and melts at 100 C. It is Well soluble in water.

The di-sulphanil ethanolamide is prepared as follows:

21.6 grams of sulphanil ethanolamide and 23.4 grams of acetanilide-p-sulphochloride are dissolved in a mixture of 150 com. acetone and 150 com. water. Ten grams sodium bicarbonate are added with stirring; the reaction takes place under development of carbon dioxide. By evaporating the acetone and addition of water the condensation compound is precipitated as a gum which solidifies on standing. The material is purified by recrystallizing out of acetic ether.

The deacetylation is made as described above. The di-sulphanil ethanolamide is crystallized out of acetic ether and melts at 131 C. It is sparingly soluble in cold water.

(2b) Glycine derivative of the di-sulphanilamide.

By using glycine instead of ethanolamin in the example given before, a glycine derivative of the di-sulphanilamide of the following constitution is attained:

HzNOS omn-O-s OzNHCHzC 0 on The glycine may be replaced by other amino acids.

(3a) Formaldehyde sulphoxylate of the di sulphanilamide.

By action of sodium formaldehyde sulphoxylate on di-sulphanilamide the water soluble formala dehyde sulphoxylate of the di-sulphanilamide is attained. The constitution is as follows:

nmsoQ-rrnsoGrmcmsmm (3b) Benzyl di-sulphanilamide.

Benzyl chloride reacts with di-sulphanilamide by substituting one hydrogen of the free amino group by the benzyl radical. The constitution of the compound thus obtained is as follows:

HzNS Oz-ONHS Oz-ONHCHzO When treated with benzyl chloride containing a carboxyl group the di-sulphanilamide delivers compounds of the following constitution:

niNs Or -@NHSOz-QNHCHzCsHKJOOH (3c) p-Aminobenzene sulphonyl 'di-sulphanilamide (caled tri-sulphanilamide) 9.8 grams of di-sulphanilamide and 7.0 grams of acetanilide-p-sulphochloride are dissolved in a mixture of 50 cc. of acetone and 50 cc. of water. 2.8 grams of sodium bicarbonate are added and the mixture is stirred for half an hour. The condensation product is precipitated with water and deacetylated as follows: 10 g. of the acetyl compound are boiled with a mixture of 40 cc. of concentrated hydrochloric acid, cc. of alcohol and 20 cc. of water for one hour. After this time bright crystal plates of the hydrochloride of the tri-sulphanilamide are formed; the

. free compound is obtained by dissolving the hymN-Osomn-OsomnO-somn.

each be built from the preceding member in the same way.

Similarly, just as the di-sulphanilamide derivatives of items 2a and 2b above, are prepared from the corresponding sulphanilamide derivatives, similar derivativesof the higher members of the series may be prepared from the corresponding derivative of the preceding member of the series.

Similarly, by following the methods by which the di-sulphanilamide salts and derivatives of items 11) and 8b, above, are prepared, like salts and derivatives of the higher members of the series may be obtained.

Thus the present invention is not limited to the particular members of the general series set forth by way of example, but in its broader aspects involves this new family of series-related root compounds and salts and derivatives thereof of the nature herein illustrated by way of example.

What we claim as new is:

l. The method of preparing therapeutically active benzene sulphonamidyl compounds of sulphanilamide which comprises condensing acetanilide para-sulphochloride with a sulphanilamide of the group consisting of sulphanilamide and its N -alkylol-, N -carboxya1kyl-, and N -phenylsulphonamide substitution products, and deacetylating the therapeutically inactive condensation product to produce a therapeutically active benzene sulphonamidyl compound of sulphanilamide.

2. The method of preparing para-aminobenzene sulphonyl-sulphanilamide by condensing sulphanilamide with acetanilide para-sulphochloride and subsequently deacetylating to render the compound therapeutically active.

3. A product of the group consisting of the N -sodium methylene sulphinate-, the N -benzyl-, and the N' -carboxybenzyl-derivatives of N [sulphanilyll sulphanilamide.

4. A method of producing sulphanilamides which comprises reacting acetylsulphanilylchloride with a sulphanilamide taken from the group consisting of sulphanilamide and its N -a1kylo1- N -carboxya1ky1-, and N -phenylsulphonamidesubstitution products, hydrolyzing and recovering the sulphanilamide produced.

5. A method of producing N -[sulphani1yl] sulphanilamide which comprises reacting acetylsulphanilylchloride with sulphanilamide, hydrolyzing and recovering the N -[sulphanilyll-sulphanilamide.

6. A method of producing N -[N -(su1phanilyl) -sulphanilyl] -su1phanilamide which comprises reacting acetylsulphanilylchloride with N -[sulphanilyll-sulphanilamide, hydrolyzing and recovering the N -[N -su1phanilyl) -sulphanilyl sulphanilamide.

'7. The alkali metal derivative of N -[su1phanilyll -sulphanilamide, said alkali metal being linked to a nitrogen of the compound.

8. The sodium derivative of N -[su]phanilyl]- sulphanilamide, having the sodium linked to a nitrogen of the compound.

9. The process which comprises reacting the compound N -[sulphanilyl]-sulphanilamide with sodium hydroxide to produce the sodium salt of the compound.

10. 4- [4'- (N sodium methylene sulphinate) aminobenzene sulphonamidol-benzene sulphonamide.

11. The process of producing new compounds which comprises reacting N -[su1phanily1] -su1- phanilamide with sodium-formaldehyde-sulphoxylate to form the N-methylene sulphinate derivative.

12. An N -[sulphani1yll-sulphanilamide alkyl carboxylic acid.

SANFORD M. ROSENTHAL. HUGO BAUER. 

